Sterile product and method for sterilizing and assembling such product

ABSTRACT

Methods are disclosed for sterilizing a selected portion of a product and for assembling a sterile product from two or more parts which can not be sterilized with the same form of sterilization. A sterile product produced by these methods is also disclosed. The method for sterilizing may include sterilizing a selected portion of the product by exposing the selected portion to an electron beam, while shielding the remainder of the product from the radiation of the electron beam. The method of assembling a sterile product from two or more component parts may include the steps of sterilizing the first part of the product, isolating a portion of the first part from the remainder of the first part, attaching the second part to the isolated portion of the first part, and exposing the isolated portion to a form of sterilization which is deleterious to the remainder of the first part, while shielding the remainder of the first part from such form of sterilization.

The present invention relates generally to sterile products and tomethods for sterilizing and assembling such products More particularly,the present invention relates to sterile products and to methods forsterilizing and assembling such products, wherein the products have twoor more portions which are mutually incompatible with regard to themethod of sterilization.

Pre-sterilized, disposable medical products are commonplace in theUnited States and other countries throughout the world. One heretoforesignificant restraint on the design, development, and manufacture ofsuch products has been the fact that certain desirable products wouldinclude portions or components which are mutually incompatible from asterilization standpoint For example, it may be desirable to provide aunitary, pre-sterilized product which has a sealed liquid or powder drugcomponent and a plastic apparatus component, such as a tubing or flowcontrol set, for dispensing the drug.

The integral product, however, cannot be sterilized after assemblybecause not all of the components may be subjected to the same form ofsterilization. For example, the plastic apparatus component (e.g. Thetubing or flow control device) may only be sterilizable with radiationor gas. The drug component, on the other hand, may not be sterilizablewith either gas or radiation----gas sterilization would be ineffectiveto sterilize a sealed drug, while exposing the drug to radiation maylead to product degradation or otherwise have a deleterious effect onthe drug.

Accordingly, efforts have been made to devise means for joining, in asterile manner, components which are individually pre-sterilized. Oneexample of such a product is the blood processing (apheresis) kitmanufactured and sold by the Fenwal division of Baxter HealthcareCorporation of Deerfield, Illinois. Typically, the blood processing kit(such as those produced by Baxter Healthcare) consists of two or morecontainers filled with medical solutions, connecting tubes, and a flowcontrol subassembly. The solution containers may be filled withanticoagulant to prevent blood clotting, dextrose as an energy sourcefor blood cells, saline, or other medical liquid utilized in thetreatment of the patient or in the collection of blood components. Anetwork of tubing connects the solution containers and the flow controlsubassembly.

The current process for manufacturing such apheresis kits involves amulti-step process of assembling an entire apheresis kit with emptysolution containers; filling separate containers with the desiredsolution; separately sterilizing the assembled kit (with the emptycontainers) and the filled containers; transferring in a sterile mannerthe pre-sterilized solution into the presterilized empty solutioncontainers; and discarding the original (now empty) solution containers.

The sterile transfer of solution is achieved through the use of asterile docking device such as the device disclosed in U.S. Pat. No.4,157,723. The sterile docking device shown there utilizes a pair ofmating halves, with facing membranes. One half of the docking device isconnected to the empty pre-sterilized containers, and the other half isconnected to the full pre-sterilized container. After the halves arejoined, the docking device is exposed to radiant energy, causing themembranes within the docking devices to melt and form a sterile fluidpathway through the device. Once this pathway is formed, the previouslysterilized solution is manually transferred from the original bag to theempty bag attached to the kit. After transfer, the transfer tubing issealed and cut, and the emptied bags and the docking devices arediscarded.

While this process has generally worked satisfactorily, it entails thestep of transferring solution from one container to another in a sterilemanner and all the extra quality control procedures associated with sucha step. Also, once the solution is transferred, the original solutionbags and sterile docking devices cannot be reused and must be discarded,adding cost to the final product.

For these reasons, it is a general object of the present invention toprovide an improved sterile product of the type described above andimproved methods for sterilizing and assembling such products.

This and other objects of the present invention are set forth in thefollowing detailed description of the illustrated embodiment of thepresent invention.

SUMMARY OF THE INVENTION

The present invention is directed generally to sterile integralproducts, to methods for assembling such products, and to methods forsterilizing a selected portion of such products. The sterile integralproduct may consist of a first portion which is unsuited to selectedforms of sterilization, such as radiation, and a second portion which isparticularly well suited to utilizing such selected forms ofsterilization. In accordance with one aspect of the present invention,the second portion of the product may be exposed to the selected form ofsterilization, while the other portion of the product is shielded fromthe selected form of sterilization. This may be performed with the twoportions integrally connected and in relatively close association witheach other.

In another embodiment of the present invention the first portion may besterilized prior to joinder with the second portion, in a manner whichachieves a sufficient degree of sterilization while not adverselyaffecting it, such as steam heat. The second portion may be sterilizedprior or subsequent to joinder with the first portion, utilizing a formof sterilization such as gas or radiation, which is unsuitable forsterilizing the first portion. The portions are joined by firstisolating a part of the first portion and attaching it to the secondportion. If the second portion is also sterilized prior to joinder, thena part of the second portion is also isolated. The isolated parts of thefirst and second portions are then joined and the joined isolatedportions, or the isolated part of the first portion and all or some ofthe second portion if the second portion is not pre-sterilized, are thensterilized in one of the selected manners, while the remainder of thefirst portion is shielded from adverse effect by such selected form ofradiation.

The isolated parts of the first and second product portions may includemeans defining a fluid flow conduit between the first and second productportions. The fluid flow conduits may be isolated from the remainder ofthe product portions by mechanical means such as clamps, valves or thelike, or by the inherent characteristics of the conduit itself, whichlimits possible ingress or movement of bacteria or organisms toward theremainder of the product portion. In any event, the isolated portionsare subjected to one of the selected forms of sterilization so as toassure sterility of the isolated portions, while the remainder of thefirst product portion is shielded to prevent adverse effects. Theisolating means may then be removed, if necessary, to yield a connectedintegral sterile product, made up of portions which are otherwisemutually incompatible from a sterilization standpoint.

In accordance with a further aspect of the present invention, thepreferred selected form of sterilization is irradiation by electronbeam. An electron beam may be easily focused on the isolated portions,readily started and stopped. An electron beam may also be readilyshielded from any personnel involved in product manufacture and/or fromthe remainder of the product which should not be exposed to radiation.

The present invention has particular application in the assembly andsterilization of medical products containing medical liquids or drugs.For example, in one version of the present invention, the first productportion includes one or more sealed containers filled with a medicalliquid or drug which is adversely affected by ethylene oxide gas and/orradiation sterilization. The second product portion may comprise anadministration apparatus which is to be directly attached to the firstportion for administering the liquid or drug to a patient. Suchadministration apparatus, however, is only sterilizable in a mannerwhich is incompatible with the fluid or drug, such as radiation orethylene oxide gas.

In accordance with the present invention, the first portion isseparately sterilized by autoclaving, i.e., steam heating, the containerand contents, while the second portion may be separately sterilized byeither gas or radiation. Once the product portions have been separatelysterilized, the product is assembled.

In one arrangement, each portion of the product includes means defininga flow path, e.g., plastic tubing, in communication with its respectiveproduct portion. In accordance with the present invention, the entireproduct is assembled by isolating at least a portion of the flow pathsfrom the remainder of the product portions and joining the isolatedsections of the flow path together. The flow path may be isolated byclamping the flow paths associated with the first and second productportions or, alternatively, by providing a normally-closed frangibleconnector in the flow path of each portion. If the flow paths have asufficiently small bore, there may also be isolation by the inherentresistance to flow within the inside of a tube, thus eliminating theneed for separate clamping or blockage of the flow path.

After joinder, the isolated fluid flow path is sterilized by exposing itto an electron beam. During exposure of the flow path to the electronbeam, the remainder of the first product portion is shielded from thebeam in order to protect the medical fluid or drug within the containerfrom any adverse effects of radiation.

Further features of the present invention will become more fullyapparent in the following description of the illustrated embodiments andfrom the appended claims.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is vertical plan view of a sterile product embodying the presentinvention and assembled and sterilized in accordance with the method ofthe present invention.

FIG. 2 is an enlarged cross-sectional view of the connected conduitswhich form a portion of the product of FIG. 1.

FIG. 3 is a cross-sectional view taken along line 3--3 of FIG. 2.

FIG. 4 is a plan view of two containers of medical liquid or the likewhich comprise a portion of the product depicted in FIG. 1.

FIG. 5 is a plan view, partially removed, of liquid administration andprocessing apparatus which forms another portion of the product depictedin FIG. 1.

FIG. 6 is a plan view of a fixture, with portions of the product of FIG.1 mounted on the fixture in the position for sterilization on isolatedportion of the product.

FIG. 7 is a diagrammatic plan view of the fixture and product portionsof FIG. 6, depicting the sterilization of the isolated portions byirradiation.

FIG. 8 is a sectional view of apparatus which may be employed incarrying out the sterilization method of the present invention.

FIG. 9 is a sectional view of alternative apparatus for performing thesterilization of the product portions depicted diagrammatically in FIG.7.

FIG. 10 is a top view of a fixture for use with the apparatus depictedin FIG. 9 for carrying out the present invention.

FIG. 11 is a side view of the fixture of FIG. 10 taken along line 11--11of FIG. 10, and depicting a medical fluid container in phantom.

FIG. 12 is a plan view of a slide clamp which may be used in thepractice of the present invention.

FIG. 13 is an enlarged plan view of the gripping area of the clamp ofFIG. 12 taken at the area designated 13 in FIG. 12.

FIG. 14 is a cross-sectional view of

the clamp of FIG. 12, taken along line 14--14.

FIG. 15 is a partial cross-sectional view of the clamp of FIG. 12,depicting the sealing action when applied to flexible plastic tubing.

The present invention is generally embodied in a product 10, and in themethods of sterilizing and assembling such product, which productincludes one or more medical liquid containers 12 and liquidadministration or processing apparatus 14. In accordance with thepresent invention, one product portion, the containers of medical liquidmay not be radiation sterilized because of deleterious product effects,and may not be gas sterilized because they are sealed containers. As aresult, the most effective sterilization for such medical liquids isautoclaving. The other product portion 14 comprises apparatus foradministering or processing the liquid contained in the containers 12.That product portion, however, is not effectively sterilized byautoclaving, but must be radiation sterilized or sterilized usingethylene oxide gas.

The product, in FIG. 1, which is depicted for purposes of illustrationonly and not for limitation, is a closed apheresis kit or circuit, whichmay be used, for example, with the CS-3000 Blood Cell Separator marketedby Baxter Healthcare Corporation of Deerfield, Ill. A typical apheresisset is shown in more detail, for example, in U.S. Pat. No. 4,410,026 toBoggs. In this particular product, container 12a is a flexible plasticbag containing a medical fluid, such as a parenteral solution or, moreparticularly, a 0.9 percent sodium chloride solution for use in theapheresis process. Container 12b is also preferably a flexible plasticbag. It may contain, for example, a blood preservative, such asanticoagulant citrate dextrose.

The bags of liquid are attached to the liquid administration orprocessing apparatus 14 through outlet ports 16 disposed at the end ofthe bag and in communication between the interior of the bag and dripchambers 18, which may be used for monitoring the flow rate of solutionfrom the bags. Flexible plastic tubing segments 20a, b and c,respectively, extend from the bottoms of the drip chambers forattachment to the liquid administration and processing apparatus 14.

The liquid administration and processing apparatus 14 comprises a rigid,plastic panel 22 which mounts flow control valves such as 24 and loopedtubing portions 26 for cooperation with rotary peristaltic pumps, whichare provided on the CS-3000 Blood Cell Separator manufactured and soldby Baxter Healthcare Corporation. The housing 22 also mounts the fluidcircuitry for controlling the flow of liquid in the overall system incooperation with the CS-3000 Blood Cell Separator. The details of thishousing and fluid circuitry system are depicted in more detail in issuedpublic patents, such as U.S. Pat. No. 4,410,026, referred to above. Tothat extent, the '026 patent is incorporated by reference herein.

The tubing segments 20a, b, and c which extend from the drip chambers ofthe medical liquid containers are joined to mating tubing segments 28a,b and c of the liquid administration or processing apparatus 14 in themanner depicted more clearly in FIGS. 2 and 3. As shown in FIG. 2,tubings 20a and 28a are joined in fluid communication by a surmountingflexible plastic sleeve 30. The end of each tubing segment 20a and 28ais inserted into the end of the flexible plastic sleeve 30 and sealed,such as by heat, sonic or solvent bonding therewithin. Solvent bonding,with a solvent such as with cyclohexanone, is simple and is presentlythe preferred method for joining the tubing segments in a sealed manner.

FIG. 3 depicts the joint of FIG. 2 in cross-section, taken along line3--3 of FIG. 2. It shows the tubing segment 20a contained within andsealed to the interior surface of the flexible sleeve 30. This drawingwill be referred to later in discussing the sterilization that takesplace in accordance with the method of the present invention.

FIGS. 4 and 5 depict the medical liquid containers 12 and the liquidadministration or processing apparatus 14, respectively, as they appearprior to joinder. More particularly, FIG. 4 depicts the containers 12aand 12b as they would appear at the time of their sterilization. Asdescribed briefly earlier, because containers 12a and 12b are sealed,gas sterilization, such as the use of ethylene oxide, may beunavailable, depending on whether the bag is gas permeable, forsterilizing these products. Moreover, radiation sterilization is notpreferred because of possible deleterious effects on the productcontents which results from the radiation. Accordingly, the containers12a and 12b are preferably autoclaved, via steam heat, to achieve orexceed the appropriate sterility level required by the United StatesFood and Drug Administration.

In contrast to the liquid containers 12, the liquid administration andprocessing apparatus 14 is preferably sterilized with radiation or gas.Because of the complex tubing circuitry and the nature of the materialsand construction of the liquid administration and processing apparatus,autoclaving is not a preferred sterilization technique for the apparatus14. Accordingly, the liquid containers 12 and the liquid administrationand processing apparatus 14 are preferably sterilized separately, by theparticular method of sterilization which is best suited for that productportion.

In accordance with the present invention, these product portions, i.e.,the liquid containers 12 and the liquid administration and processingapparatus 14, are preferably joined in a manner which does not requireresterilization or sterilization of the entire combined product. Such,of course, would be impractical because the product portions, that isthe medical liquid containers 12 and the liquid administration andprocessing apparatus 14, are mutually incompatible insofar as thesterilization method is concerned.

As diagrammatically illustrated in FIGS. 6 and 7, the product portionsare joined by first isolating a terminal end portion of the tubingsegments 20a-c and 28a-c from the remainder of the particular productportion. For example, the terminal end of tubing 20a is isolated fromthe remainder of the tubing and the associated drip chamber. "Isolation"means blockage of the tubings from ingress by bacteria or other airbornemicroorganisms. In the preferred embodiment, the terminal end portionsof the tubings 20a and 28a are isolated from the remainder of the tubingand the product portions by removable plastic, radiation permeable slideclamps 32. Alternatively, the end portions may be isolated by internalfrangible closures, such as those depicted in U.S. Pat. Nos. 4,181,140and 4,294,247. Such frangible closures would normally seal the tubing,and would be open only after joinder and sterilization of the joined,isolated regions were complete. Regardless of whether slide clamp,internal frangible closures or other means are used for isolating theterminal end portions of the tubing, preferably the material used forsuch clamps or closures would be as nearly radiation transparent aspossible to assure that the terminal end portions, in their entirety,including any portions contained within the clamps themselves, would besterilizable by radiation in general, and electron beam radiation inparticular.

The presently preferred slide clamp 32 is depicted in more detail inFIGS. 12 through 14. The depicted slide clamp has previously been soldby the Fenwal Division of Baxter Healthcare Corporation, under productcode no. 4R4423, for use in the collection and laboratory processing ofblood and blood components. The slide clamp acts as a flow occlusiondevice, similar to a hemostat. By placing the clamp on the outside ofthe tubing, the interior walls of the tubing are compressed, therebyoccluding flow while theoretically maintaining sterility of the fluidpath beyond the slide clamp (as shown, e.g., in FIG. 15).

In the present application, the slide clamp is utilized for clamping thetubing segments 20a-c and 28a-c, tubing which preferably has an insidediameter of 0.095+/- 0.003 inches and an outside diameter of 0.146 +/-0.002 inches. The portion of the slide clamp for clamping the tubing,depicted enlarged in FIG. 13, preferably has a gap opening of 0.026inches with a tolerance of + 0.005 and -0.004 inches).

When tubing with the above-identified dimensions is placed in theclamping or gripping portion of the clamp, the tubing is tightly grippedand sealed with a compressive force which is believed to beapproximately 175 pounds per square inch. FIG. 15 depicts the grippingaction in more detail, with the area depicted by numeral 33, being arepresentation of the compressed portion of the tubing wall, beingcompressed by the clamp jaws 35.

Before describing the actual steps involved in sterilization, however,there is one further alternative for isolating the terminal end portionsof the tubing segments. Under normal assembly conditions, particularlythose associated with clean room environments, microorganism ingressinto open tubing would occur only in the terminal end portion, and theremainder of the tube and the product portion would remain sterile byreason of the static condition of air within the tube and the inherentresistance to flow of microorganisms into the tube through the openterminal end. Thus, under these conditions, a positive barrier may noteven be required to prevent contamination of the remainder of theproduct. However, slide clamps, internal frangible closures and the likehave the advantage of providing a positive barrier to ingress ofbacteria or microorganisms and are preferred at the present time.

In accordance with the present invention, the end segments of thetubings 20a-c and 28a-c are isolated by slide clamps 32 prior tojoinder. The sterile end covers 34 (FIGS. 4 and 5) of each tubingsegment are then removed and the ends of the tube are inserted into theflexible plastic sleeve 30 and solvent sealed therewithin. Followingthat step, the tubing is preferably mounted on a fixture 36, such asthat generally shown in FIG. 6. As may be seen there, the tubing is heldin place by a pair of tubing retainers 38, with the tubing sleeve 30 andslide clamps 32 positioned between the retainers.

The fixture 36, with the tubing segments positioned thereon, is thenexposed to a radiation source 40, as is figuratively shown in FIG. 7.The radiation source 40 is preferably an electron beam. During theradiation of the isolated tubing end portions, the remainder of theproducts, and in particular the medical liquid containers 12 areshielded from the radiation effects of the electron beam by an aluminumwall 39 or the like, while they remain connected to the liquidadministration and processing apparatus 14.

Electron beam radiation is particularly advantageous in thisapplication. Electron beams are unidirectional and may be relativelynarrowly focused. Also they may be readily turned on and off----unlikegamma radiation sources, which of course decay continuously whether ornot actually being used for product sterilization. Further, radiationfrom the electron beam may be readily shielded from other portions ofthe product and from personnel involved in connection with themanufacture of the product.

An accelerator such as a linear accelerator is used to generate theelectron beam. Various studies have been completed to determine theappropriate power and radiation requirements to achieve sterilization,particularly at the juncture of the tubing segments and sleeve 30, wherethere is a double wall thickness, as shown in FIG. 3.

Initial studies were conducted using a 0.6 MeV pulsed power electronbeam instrument manufactured by pulse Sciences, Inc. Connection tubingswere fabricated from radiation grade polyvinylchloride plastic of sizetypical for medical fluid administration apparatus, such as set forthabove. Far West Technology (FWT) dosimeters (FWT-60-00, batch 6FM) and aFWT Radiachromic Reader were used to quantify radiation dose.

Radiation-resistant spores of Bacillus pumilus were utilized as abiological indicator The D-value of this organism is 0.15 Mrad asdetermined by Cobalt 60 irradiation of paper strips. The sporesuspensions were prepared by North American Science Associates, Inc.,Northwood, Ohio. For the dosing studies, intact, previously sterilizedtubings were placed in an isolation fixture and clamped. Ten microliters(approximately 10⁶ spores) of the suspension of test organisms wereplaced in the interior of the tubing at a fixed site. Each tubing wasthen cut at that site and subsequently rejoined using a larger diametertubing sleeve and joined together using cyclohexanone. In someinstances, approximately 10⁶ spores were placed inside of each cuttubing half at the location of the clamps (refer to FIG. 6) prior totubing reconnection. The tubing was then allowed to remain in thefixture of a minimum of twenty-four hours (in the actual manufacturingprocess the units will be sterilized immediately after the connection ismade) after which the fixture and tubing were exposed to varying dosesof irradiation from a 0.6 MeV electron beam accelerator. A Faraday cupwas used to measure the dose delivered to the outside of the tubing andfilm dosimeters (FWT) were used to quantify doses at various locationswithin the tubing. Following irradiation, the inoculated tubings wereaseptically removed from the pouches and the inoculated areasindividually transferred to 10 ml of sterile water. After sonificationfor ten minutes, serial dilutions were made and samples were cultured at30-35 C on tryptic soy agar plates. Inoculated but non-irradiatedtubings were used as positive controls.

Results are shown in Table 1. Completed bacterial inactivation was seenat the distal (clamp region) tubing inoculation sites following 2.2Mrads of radiant energy, however, this dose was insufficient to achievesterilization at the tubing center, due to reduced electron penetrationof the double wall thickness tubing (sleeve) at the site of connection.These studies thus indicated that a higher energy electron beam would berequired for effective sterilization.

A second series of studies was performed to evaluate different beamenergies/doses. A Pulserad 122A linear electron beam accelerator ratedat 1.8 MeV was used for these studies; energy levels of 1.1, 0.9 and0.75 MeV were evaluated.

To study the variation of beam intensity at various locations within theisolation fixture, dosimeters were placed at the following locations:center of beam, 1 1/2 inches above center, 1 1/2 inches beneath center,within the single walled tubing and within the double walled "sleeve"area of the connection. Approximately 0.5 Mrad was delivered to thetubing contained within the fixture in each of two separate experiments.As shown in Table 2, approximately one-half of the dose delivered to theoutside center of the tube was available at the interior of the doublewalled connection area (=0.31 Mrad). About a 50% falloff in dose alsooccurred from the beam center to beam periphery. The delivered radiationdose of the beam is gaussian with intensity at the periphery beingapproximately 50% of the intensity at the center. Since a higher dose isrequired in the center double wall (sleeve) area due to materialthickness, the observed pattern of energy delivery seemed well suitedfor the application.

Additional studies were performed using B. pumilus pores as a biologicalindicator. For each dose study, three tubings were placed in theisolation fixture and positioned as would be the case during apheresiskit manufacture. Two tubings were used for inoculation studies whiledosimeters were placed within the double-walled central tubing area(junction site) and within the tubing lumen at the clamp occlusion siteof the third. A dosimeter was also placed in a paper envelope andattached to a Faraday cup.

Approximately 6.2 × 10⁵ B. pomilus spores were placed at the intendedsite of reconnection under the double-wall portion of tubing. Anadditional 8-9× 10⁵ B. pumilus spores were placed within the interior ofeach tubing at the points at which it was clamped. After the connectionhad been made, the tubings and fixture were irradiated using a beamenergy of 1.1 MeV. Additional studies were performed using differenttubings, inocula and dosimeters; the delivered (exterior) dose in thesestudies ranged from 0.45 to 6.00 Mrads.

Table 3 shows that while viable biological indicator organisms wererecovered when the tubings were exposed to a low dose at an energy of1.1 MeV irradiation (external dose =0.45 and 1.05 Mrads, respectively),no organisms were recovered from the inoculated sites following externaldoses of 2.38 Mrads or more. Culture of non-irradiated control samplesshowed recoveries of from 6 to 9 × 10⁵ viable organisms. Table 3 showsbacterial recovery following various doses of electron beam irradiation.Since the D value for B pumilus is 0.15 Mrad, a total dose of 0.15×6=0.9 Mrad would be anticipated to be needed for a 6-log reduction ofviable organisms. The third incremental dose delivered (1.35 Mradsinside the double wall connection area) exceeded the anticipated (0.9Mrads) dose required for 6-log organism reduction. Thus, with anexternal dose of 2.38 Mrads and a delivered (Worst case) internal doseof 1.35 Mrads, a spore log reduction of 9 was seen within thefluid-contact pathway. Based on anticipated product and manufacturingfacility bioburden data, a sterility assurance level of in excess of10⁻¹⁶ may be anticipated.

Additional dose/biological indicator studies using 0.9 MeV and 0.75 MeVbeam energies were also conducted in a similar manner. At both beamenergies, no viable organisms remained following delivery of 2.5 or moremegarads of energy (Table 4).

While the above demonstrates the effectiveness of beam energies as lowas 0.75 MeV with 2.5 or more megarads of delivered energy, preferably a2.0 MeV linear electron beam acceleration will be used in actualproduction.

Calculations also demonstrated that a 10 mm thick aluminum sheet wouldbe expected to be adequate to shield products from 4.5 MeV electrons.This shield thickness is expected to be adequate at both 2.5 and 5.0Mrad doses.

Subsequently, specific dosimetry and biological indicator studies wereperformed to quantify the radiation dose delivered to portions of theapheresis kit and solutions external to the isolation fixture/tubingtarget area. In these studies, dosimeters and B. pumilus biologicalindicator strips were placed on the solution containers. The connectedtubing region and the shielded isolation fixture were then subjected to2.5 Mrad or 5.0 Mrad doses of electron beam irradiation as would takeplace during the manufacturing technique No radiation was found to bedelivered to the solution containers at either dose of incidentradiation (lower limit of dosimeter detection =0.05 Mrad). Nosignificant differences were seen in organism recovery betweennon-irradiated and shielded/irradiated biological indicator strips,further indicating the adequacy of solution fixture shielding using 10mm aluminum.

Based upon the above, solution stability/dating is unlikely to beadversely affected by this change in the apheresis kit manufacturingprocess. Assay of non-irradiated control and shielded/irradiatedsolutions exposed to 2.5 and 5.0 Mrad doses of radiation did not showsignificant changes in solution constituents as shown in Table 5.

Apparatus for carrying out the present invention is depicted in FIGS. 8through 11. FIG. 8 shows an electron sterilization unit having aradiation source 40, radiation shielded housing 42 and a conveyor 44 forloading and unloading the fixture 36 within the radiation shieldedhousing 42. As depicted there, the fixture 36 is mounted atop a carrier46 adapted to move along the top of the roller conveyor 44. The product10, which comprises the medical liquid containers 12 and liquidadministration or processing apparatus 14 lies atop the carrier. Thetubings 20a-c and 28a-c are fixed in the isolation fixture 36 in theposition indicated in FIG. 6.

After the carrier 46 enters the housing 42, it is raised by a pistoncylinder arrangement 48 into the position indicated in dashed lines inFIG. 8. The walls of the isolation fixture 36 surround the electron beamemitter and isolate the remaining portions of the product, particularlythe medical liquid containers 12, from the radiation resulting from theelectron beam. After the carrier is raised to the position shown indashed lines, the electron beam is turned on to provide the appropriateradiation dose, as discussed in detail above and shown in the precedingtables, to assure sterility of the tubing area between the isolatingclamps. Following sterilization, the carrier is lowered and removed fromthe housing along the roller conveyor 44.

FIG. 9 depicts an alternative embodiment of apparatus which may be usedfor carrying out the present invention, which does not require as muchshielding as the apparatus of FIG. 8, and is believed to be moreefficient in its operation. The apparatus depicted in FIG. 9 includes ashielded housing 50, a conveyor 52 upon which product carrier plates 54move and a shielded closure member 56 mounted for vertical movement byan air or hydraulic cylinder 58.

The detailed construction of the product carrier plate is best seen inFIGS. 10 and 11. The carrier plate has a generally rectangular, flatsurface 58 upon which the medical liquid containers 12 and the liquidadministration apparatus 14 rest. The tubings 20a-c and 28a-c lie alongan outwardly extending and arcuate arm 60 with the flexible plasticsleeves 30 disposed at the end of the arm over a U-shaped aperture.

After the product is placed upon the carrier and the tubing arranged inthe manner depicted in FIGS. 10 and 11, the carrier is moved into theposition shown in FIG. 9 relative to the shielded housing. The lowerclosure member 56 is then moved upwardly, nesting tightly against and onthe underside of the arm 60. As can be seen from FIG. 9, the end portionof the arm, where the joining flexible plastic sleeves 30 are located ispositioned at a lower aperture 62 of the shielded housing which is thefocus of the electron beam The beam is then energized, as describedabove, to effect sterilization of the isolated portion of the tubings20a-c and 28a-c. The closure member 56 is then lowered and the carrierremoved from the housing along the conveyor 52. The next carrier is thenmoved into place and these steps are repeated.

The apparatus disclosed in FIGS. 9 through requires less shielding thanthat depicted in FIG. 8 due, in part, to the arcuate arm 60 (best seenin FIG. 11). The arcuate nature of the arm 60 creates a non-linearserpentine path which greatly restricts the emission of any radiationfrom the isolated tubing area.

Although the present invention has been described in terms of thepreferred embodiment and utilizing a specific product as an example ofhow it may be employed, the present invention is not limited to theparticular product depicted in FIG. 1 or to the apparatus shown in theother drawings. The scope of the present invention is defined by theappended claims.

                                      TABLE 1                                     __________________________________________________________________________    CENTER (DOUBLE THICKNESS [REJOINED] AREA)                                                      TYPICAL        END (CLAMP LOCATION)                                           INTERIOR       ORGANISMS                                     SURFACE DOSE                                                                            FARADAY                                                                              OF TUBING                                                                            ORGANISMS                                                                             REMAINING*                                    (FILM)    CUP    DOSE   REMAINING                                                                             END A  END B                                  __________________________________________________________________________    1.00 Mrad  .55 Mrad                                                                            .15 Mrad                                                                             3 × 10.sup.3                                                                    1 × 10.sup.3                                                                   4 × 10.sup.3                     1.50 Mrad 1.10 Mrad                                                                            .25 Mrad                                                                             2 × 10.sup.3                                                                    9 × 10.sup.1                                                                   4 × 10.sup.4                     2.20 Mrad 2.20 Mrad                                                                            .55 Mrad                                                                             1 × 10.sup.4                                                                    4 × 10.sup.2                                                                   0                                      >2.20 Mrad                                                                              3.30 Mrad                                                                            .80 Mrad                                                                             3 × 10.sup.1                                                                    0      0                                      __________________________________________________________________________     * = 4 × 10.sup.5 Bacillus pumilus spores recovered from                 nonirradiated control areas.                                             

                  TABLE 2                                                         ______________________________________                                                      DELIVERED DOSE (Mrad)                                           DOSIMETER POSITION                                                                            STUDY A     STUDY B                                           ______________________________________                                        Outside Center  .55         .50                                               Outside Top     .31         .31                                               Outside Bottom  .31         .31                                               Within Double Wall                                                                            .31          .22*                                             Within Single Wall                                                                            --           .27*                                             ______________________________________                                         *Tubing center was 1/2 inch off beam center.                             

                                      TABLE 3                                     __________________________________________________________________________    BIOLOGICAL INDICATOR COUNT*                                                   DOSE (Mrad)                                                                         INSIDE                                     SPORE LOG                    OUTSIDE                                                                             DOUBLE                                                                              TUBING 1          TUBING 2           REDUCTION                    TUBE  WALL  CENTER                                                                              CLAMP A                                                                             CLAMP B                                                                             CENTER                                                                              CLAMP A                                                                             CLAMP B                                                                              EXPECTED                                                                             ACTUAL                __________________________________________________________________________    0.45  .23   9.0 × 10.sup.3                                                                3.0 × 10.sup.4                                                                1.0 × 10.sup.4                                                                2.0 × 10.sup.3                                                                3.0 × 10.sup.3                                                                2.0 × 10.sup.4                                                                  1.50  2.00                                                                          (1.5 -                                                                        2.6)                  1.05  .575  1.5 × 10.sup.1                                                                4.0 × 10.sup.2                                                                6.0 × 10.sup.1                                                                2.0 × 10.sup.1                                                                6.0 × 10.sup.2                                                                8.0 × 10.sup.2                                                                  3.80  3.80                                                                          3.0 -                                                                         4.6)                  2.38  1.35  0     0     0     0     0     0       9.00  --                    3.05  1.60  0     0     0     0     0     0      11.00  --                    3.50  1.75  0     0     0     0     0     0      12.00  --                    4.43  2.43  0     0     0     0     0     0      16.00  --                    4.80  2.50  0     0     0     0     0     0      17.00  --                    6.00  3.50  0     0     0     0     0     0      23.00  --                    __________________________________________________________________________     *Controls: Center: 6.2 × 10.sup.5 Clamp A: 9.2 × 10.sup.5         Clamp B: 8.0 × 10.sup.5                                            

                                      TABLE 4                                     __________________________________________________________________________    BIOLOGICAL INDICATOR COUNT                                                    DOSE (Mrad)                                                                        Inside                                                                            Inside          % OUTSIDE DOSE                                       Outside                                                                            Double                                                                            Single                                                                            TUBING 1                                                                            TUBING 2                                                                            PRESENT INSIDE                                       Tubing                                                                             Wall                                                                              Wall                                                                              Center                                                                              Center                                                                              DOUBLE WALL TUBING                                   __________________________________________________________________________    BEAM ENERGY: 0.9 MeV                                                          1.30 1.05                                                                              1.20                                                                              1.5 × 10.sup.4                                                                6 × 10.sup.1                                                                  81%                                                  2.50 2.03                                                                              2.30                                                                              0     0     81%                                                  3.48 2.77                                                                              3.18                                                                              0     0     80%                                                  BEAM ENERGY: 0.75 MeV                                                         0.90  .65                                                                              .875                                                                              3 × 10.sup.2                                                                  8     72%                                                  2.65 1.85                                                                              --  0     0     70%                                                  4.85 2.83                                                                              4.28                                                                              0     0     58%                                                  __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Changes in Solution Constituents Following                                    Shielded Exposure to 2.5 and 5.0 Mrads of                                     Electron Beam Radiation                                                       PRODUCT                                                                              TEST       CONTROL 2.5 Mrad                                                                              5.0 Mrad                                    __________________________________________________________________________    0.9% NaCl                                                                            pH (Unbufferred)                                                                         6.00    4.80    4.40                                               Chloride (g/L)                                                                           9.05 ± 0.2                                                                         9.13 ± 0.2                                                                         9.06 ± 0.2                                      Sodium (ID)                                                                              POS     POS     POS                                         ACD    Sodium Citrate (g/L)                                                                     22.2 ± 0                                                                           22.2 ± 0.3                                                                         22.1 ± 0.3                                      Citric Acid (g/L)                                                                        7.32 ± 0.1                                                                         7.32 ± 0.1                                                                         7.31 ± 0.1                                      Dextrose (%)                                                                             2.47    2.47    2.49                                               pH         4.90    4.90    4.90                                               Chloride   NMT 20 PPM                                                                            NMT 20 PPM                                                                            NMT 20 PPM                                  __________________________________________________________________________

What is claimed is:
 1. A method for assembling a sterile product havingat least two parts, comprising;sterilizing the first part of saidproduct; isolating a selected portion from the remainder of said firstpart; attaching a second part of said product to said selected portion;exposing said selected portion to an electron beam sufficient to effectsterilization of said portion; and shielding the remainder of said firstpart from the radiation of said electron beam.
 2. The method of claim 1wherein said selected portion of said first part comprises meansdefining a fluid flow path.
 3. The method of claim 1 further comprisingthe step of sterilizing the second part.
 4. The method of claim 1wherein the step of sterilizing the first part portion is carried out byheating.
 5. The method of claim 1 wherein said first part comprisesmeans defining a container having contents therein and said selectedportion comprises means defining a fluid flow path for allowing flow offluid to or from said container.
 6. The method of claim 5 wherein thestep of sterilizing said container and contents is carried out withoutmaterially adversely affecting said contents.
 7. The method of claim 1wherein the step of sterilizing said container and contents is carriedout by heating said container and contents.
 8. The method of claim 1wherein said shielded remainder includes a material which would bematerially adversely affected by exposure to the radiation of saidelectron beam.
 9. A method of assembling a sterile integral producthaving a first portion, a part of which is substantially adverselyaffected by exposure to a selected form of sterilization and a secondportion which is not adversely affected by such form of sterilization,said method including the steps of:sterilizing said first portion priorto joinder to said second portion without substantially adverselyaffecting said first portion; isolating selected area of said firstproduct portion which is not adversely affected by exposure to aselected form of sterilization; joining said second product portion tosaid first product portion at said selected area; exposing at least saidselected area to said selected form of sterilization while said firstproduct portion is in relative close association with said secondportion; and shielding said first portion form said selected form ofsterilization.
 10. The method of claim 9 wherein said selected form ofsterilization is exposure to an electron beam.
 11. The method of claim 9wherein said first product portion includes a container with contentstherein and said second product portion includes means defining a fluidflow path for allowing flow to or from said container.
 12. The method ofclaim 11 wherein said first product portion is sterilized by heating andsaid selected form of sterilization includes exposure to radiation. 13.The method of claim 11 wherein said first product portion comprises aplastic container having a medical liquid therein and said secondproduct portion comprises a plastic tube attached to said container forallowing flow to or from said container.
 14. A method for assembling asterile integral product having a first portion and a second portion,each portion having means defining a flow path communicating with saidrespective portion, said flow path defining means being joined toprovide a flow path between said first and second portion, said methodincluding the steps of:sterilizing said first portion prior to joinderto said second portion; sterilizing said second portion prior to joinderto said first portion; isolating said flow path defining means from therespective remainder of each of said portions prior to joinder; joiningsaid flow path defining means subsequent to isolation to provide a flowpath between said first and second portions; sterilizing said flow pathdefining means after joinder; shielding selected parts of said first andsecond portions from the effect of the sterilizing of said flow pathdefining means during said sterilizing.
 15. The method of claim 14wherein said first portion is sterilized by applying heat, said secondportion is sterilized by a method selected from the group consisting ofradiation sterilization and gas sterilization, and said flow pathdefining means is sterilized by exposure to an electron beam.
 16. Themethod of claim 15 wherein said first portion includes a container withmedical fluid therein.
 17. The method of claim 15 further comprising thestep of opening the flow path to provide communication between saidfirst and second portions.
 18. The method of claim 14 wherein said stepof isolating said flow path defining means includes the step of clampingthe flow paths associated with the first and second portions to isolatethem from contamination.
 19. The method of claim 14 wherein said step ofisolating is achieved by providing a normally-closed frangible connectorin the flow path of each portion.
 20. A method for assembling a sterileintegral product comprising:providing a first product portion includingplastic container with contents therein and a fluid flow conduitextending therefrom; providing a second product portion including afluid flow conduit; sterilizing said first product portion withoutmaterially adversely affecting the container contents; sterilizing thesecond product portion in a manner which would adversely affect thecontainer contents; joining the end portions of said fluid flow conduitsto provide for communication between said first and second productportions; the fluid flow conduits to an electron beam a sufficient timeto sterilize the end portions; shielding the first product portion formthe electron beam during sterilization of said conduit end portions.